Anti-diabetic and anti-adipogenic effects of a novel selective 11 beta-hydroxysteroid dehydrogenase type 1 inhibitor in the diet-induced obese mice

作者：Park Ji Seon; Rhee Sang Dal; Jung Won Hoon; Kang Nam Sook; Kim Hee Youn; Kang Seung Kyu; Ahn Jin Hee; Kim Ki Young^*

来源：European Journal of Pharmacology, 2012, 691(1-3): 19-27.

DOI：10.1016/j.ejphar.2012.06.024

• 11 beta-Hydroxysteroid dehydrogenase type 1
• Type 2 diabetes
• Adipogenesis
• Insulin sensitivity
• Glucose tolerance

Glucocorticoid excess (Cushing%26apos;s syndrome) causes metabolic syndrome such as visceral obesity, insulin resistance, diabetes mellitus, dyslipidaemia and hypertension. The selective inhibitors of 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) have considerable potential for treating type 2 diabetes mellitus and metabolic syndrome. In the present study, we investigated the anti-diabetic and anti-adipogenic effects of 4-(2-(1,1-dioxido-6-(2,4,6- trichlorophenyl)-1,2,6-thiadiazinan-2-yl)acetamido)adamantane-1-carboxamide (KR-67183), a novel selective 11 beta-HSD1 inhibitor; we also investigated the underlying molecular mechanisms in the cortisone-induced 3T3-L1 adipogenesis model system and diet-induced obese (DIO) mice. KR-67183 concentration-dependently inhibited 11 beta-HSD1 activity in human and mouse 11 beta-HSD1 over-expressed cells and in the ex vivo assay of C57BL/6 mice. In the study with DIO mice, the administration of KR-67183 (20 and 50 mg/kg/day, orally for 28 days) improved the glucose tolerance and insulin sensitivity with suppressed 11 beta-HSD1 activity in the liver and fat. However, KR-67183 showed no change in the adrenal gland weight/body weight ratio and plasma corticosterone concentration in DIO mice. Further, KR- 67183 suppressed adipocyte differentiation on cortisone-induced adipogenesis in 3T3-L1 cells is associated with the suppression of the cortisone-induced mRNA levels of FABP4, PPAR gamma 2 and GLUT4, and 11 beta-HSD1 activity. Taken together, it is suggested that a selective 11 beta-HSD1 inhibitor, KR-67183, may provide a new therapeutic window in the prevention and treatment without toxicity in type 2 diabetes with obesity.

• 出版日期2012-9-15